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Veterinary Sciences Aug 2023Cyclooxygenase (COX) inhibitors have been demonstrated to have antitumour activity in canine urothelial cell carcinoma (UCC), given as a sole treatment or in combination...
Cyclooxygenase (COX) inhibitors have been demonstrated to have antitumour activity in canine urothelial cell carcinoma (UCC), given as a sole treatment or in combination with chemotherapy. The purpose of this retrospective multi-institutional study was to assess the efficacy of meloxicam in combination with mitoxantrone or vinblastine as a first-line treatment for non-resectable canine UCC. Gastrointestinal adverse effects (AEs) of these treatment combinations were also assessed. A total of 28 dogs met the inclusion criteria, 21/28 dogs received mitoxantrone and meloxicam, and 7/28 received vinblastine and meloxicam. Tumour response (TR) and AE were evaluated according to Veterinary Co-Operative Oncology Group (VCOG) criteria. The endpoint of the study was the time to tumour progression (TTP). The mitoxantrone-group induced 24% partial response and 62% stable disease, while the vinblastine-group induced 14% and 86%, respectively. Median TTP was 84 days (mitoxantrone and meloxicam, 70 days; and vinblastine and meloxicam, 178 days). The presence of metastatic disease significantly decreased TTP ( = 0.007). Gastrointestinal AEs were reported in 21.4% of the patients, with the most common being VCOG grade 1-2 diarrhoea. Meloxicam is a well-tolerated NSAID when combined with mitoxantrone or vinblastine as first-line treatment for non-resectable canine UCC.
PubMed: 37624316
DOI: 10.3390/vetsci10080529 -
Blood Advances Sep 2023The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective...
The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Cytarabine; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Mitoxantrone; Sorafenib; Middle Aged
PubMed: 37339483
DOI: 10.1182/bloodadvances.2023010392 -
ACS Chemical Biology Jun 2023The combination of doxorubicin (Adriamycin) and cyclophosphamide, referred to as AC chemotherapy, is commonly used for the clinical treatment of breast and other...
The combination of doxorubicin (Adriamycin) and cyclophosphamide, referred to as AC chemotherapy, is commonly used for the clinical treatment of breast and other cancers. Both agents target DNA with cyclophosphamide causing alkylation damage and doxorubicin stabilizing the topoisomerase II-DNA complex. We hypothesize a new mechanism of action whereby both agents work in concert. DNA alkylating agents, such as nitrogen mustards, increase the number of apurinic/apyrimidinic (AP) sites through deglycosylation of labile alkylated bases. Herein, we demonstrate that anthracyclines with aldehyde-reactive primary and secondary amines form covalent Schiff base adducts with AP sites in a 12-mer DNA duplex, calf thymus DNA, and MDA-MB-231 human breast cancer cells treated with nor-nitrogen mustard and the anthracycline mitoxantrone. The anthracycline-AP site conjugates are characterized and quantified by mass spectrometry after NaB(CN)H or NaBH reduction of the Schiff base. If stable, the anthracycline-AP site conjugates represent bulky adducts that may block DNA replication and contribute to the cytotoxic mechanism of therapies involving combinations of anthracyclines and DNA alkylating agents.
Topics: Humans; Anthracyclines; Schiff Bases; DNA; DNA Damage; Topoisomerase II Inhibitors; Doxorubicin; Antibiotics, Antineoplastic; Alkylating Agents; Cyclophosphamide; DNA Repair; DNA Adducts
PubMed: 37200590
DOI: 10.1021/acschembio.3c00033 -
Journal of Veterinary Internal Medicine Mar 2021Locoregional tumor control and prolonged survival for dogs with genitourinary carcinoma (CGUC) reportedly are achievable using treatment with radiotherapy (RT) with or...
BACKGROUND
Locoregional tumor control and prolonged survival for dogs with genitourinary carcinoma (CGUC) reportedly are achievable using treatment with radiotherapy (RT) with or without adjunctive chemotherapy and nonsteroidal anti-inflammatory drugs (NSAIDs).
OBJECTIVES
To characterize event-free and overall survival after treatment of CGUC using NSAIDs, mitoxantrone (MTX), and a standardized RT protocol (57 Gy in 20 fractions).
ANIMALS
Fifty-one client-owned dogs treated between 2008 and 2017.
METHODS
Dogs were retrospectively categorized into treatment groups: (a) first-line concurrent chemoradiotherapy (≥1 dose of MTX started within 1 month of RT); (b) first-line chemotherapy (MTX administered for >1 month before RT without tumor progression); (c) RT as a salvage procedure (MTX, surgery or both with subsequent locoregional tumor progression before RT). Treatment-induced toxicoses, event-free survival (EFS), and overall survival times (OSTs) were recorded. The influence of demographics, staging, and treatment-related factors on survival was assessed using Cox proportional hazards modeling.
RESULTS
Median EFS and OST for all dogs were 260 and 510 days with no significant differences among groups 1 (n = 39), 2 (n = 4), and 3 (n = 8). Both EFS and OST were shorter in dogs with moderate to severe clinical signs (P < .001 and P < .001, respectively); OST was shorter in dogs with prostatic involvement (P = .02). Permanent urinary incontinence developed in 16 dogs (31%) at a median of 70 days postirradiation; other toxicoses were mild and self-limiting.
CONCLUSIONS AND CLINICAL IMPORTANCE
Mild clinical signs and lack of prostate involvement were associated with favorable prognosis for survival. Client education regarding the risk of urinary incontinence is warranted.
Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Carcinoma; Dog Diseases; Dogs; Male; Mitoxantrone; Neoplasm Staging; Pharmaceutical Preparations; Retrospective Studies; Treatment Outcome
PubMed: 33634516
DOI: 10.1111/jvim.16078 -
American Journal of Cancer Research 2021Adenoid cystic carcinoma (ACC) is a slow growing, but relentless cancer. Due to its rarity and lack of understanding of its molecular etiology, no standard chemotherapy... (Review)
Review
Adenoid cystic carcinoma (ACC) is a slow growing, but relentless cancer. Due to its rarity and lack of understanding of its molecular etiology, no standard chemotherapy for ACC currently exists and many patients suffer from recurrent and/or metastatic disease. As such, development of safe and effective therapies is imperative. To describe and summarize existing clinical trial studies and preclinical discoveries, we surveyed the PubMed on developmental therapeutics for ACC. Objective response rates to monotherapy with cytotoxic agents were approximately 10% with cisplatin, 5-FU, gemcitabine, mitoxantrone, epirubicin, vinorelbine and paclitaxel. The most studied combination therapies were cyclophosphamide-doxorubicin-cisplatin (CAP) and cisplatin-vinorelbine, with an objective response rate of 18-31%. Among molecularly targeted drugs, the most studied drugs are inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) to inhibit tumor angiogenesis. Among those, lenvatinib and axitinib showed a relatively high objective response rate of 11-16% and 9-17%, respectively. Given high recurrence rates and chemoresistance of ACC, treatments targeting cancer stem cells (CSC), which function as tumor-initiating cells and drive chemoresistance, may be particularly valuable. CSC have been shown to be targetable via MYB, Notch1, p53 and epigenetic mechanisms. Myb overexpression is characteristic in ACC but was previously thought to present a difficult target due to its nature as a transcription factor. However, due to the development Myb-targeted inhibitors and an ongoing clinical trial of MYB-targeted cancer vaccine therapy, MYB is becoming an increasingly attractive therapeutic target. Drugs targeting NOTCH signaling demonstrated 5-17% response rate in phase I clinical trials. Within the field of epigenetics, treatment with PRMT5 inhibitors has shown 21% partial response rate in phase I clinical trial. Immunotherapies, such as PD-1 inhibitors, are also associated with CSC, but have not been effective against ACC. However, clinical trials of cancer vaccine therapies are actively being conducted. In addition to conventional chemotherapies and inhibitors of angiogenesis, the emergence of new therapies such as immunotherapy and those targeting cancer stemness is expected to bring clinical benefits to patients in the future.
PubMed: 34659878
DOI: No ID Found -
Redox Biology Nov 2023NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC),...
OBJECTIVE
NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2 ESCC.
DESIGN
We performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. The mechanism of action of one compound was explored by biochemical assays.
RESULTS
Using high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified concentrations. We then validated two of these compounds, pyrimethamine and mitoxantrone, by demonstrating their dose- and time-dependent inhibitory effects on the expression of NRF2 and its target genes in two NRF2 human ESCC cells (KYSE70 and KYSE180). RNAseq and qPCR confirmed the suppression of global NRF2 signaling by these two compounds. Mechanistically, pyrimethamine reduced NRF2 half-life by promoting NRF2 ubiquitination and degradation in KYSE70 and KYSE180 cells. Expression of an Nrf2 allele in mouse esophageal epithelium (Sox2CreER;LSL-Nrf2) resulted in an NRF2 phenotype, which included squamous hyperplasia, hyperkeratinization, and hyperactive glycolysis. Treatment with pyrimethamine (30 mg/kg/day, p.o.) suppressed the NRF2 esophageal phenotype with no observed toxicity.
CONCLUSION
We have identified and validated pyrimethamine as an NRF2 inhibitor that may be rapidly tested in the clinic for NRF2 ESCC.
Topics: Humans; Animals; Mice; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; NF-E2-Related Factor 2; Pyrimethamine; Hyperplasia; Cell Line, Tumor; Cell Proliferation
PubMed: 37776708
DOI: 10.1016/j.redox.2023.102901 -
BMC Cancer Sep 2023Cardiotoxicity is among the most important adverse effects of childhood cancer treatment. Anthracyclines, mitoxantrone and radiotherapy involving the heart are its main...
BACKGROUND
Cardiotoxicity is among the most important adverse effects of childhood cancer treatment. Anthracyclines, mitoxantrone and radiotherapy involving the heart are its main causes. Subclinical cardiac dysfunction may over time progress to clinical heart failure. The majority of previous studies have focused on late-onset cardiotoxicity. In this systematic review, we discuss the prevalence and risk factors for acute and early-onset cardiotoxicity in children and adolescents with cancer treated with anthracyclines, mitoxantrone or radiotherapy involving the heart.
METHODS
A literature search was performed within PubMed and reference lists of relevant studies. Studies were eligible if they reported on cardiotoxicity measured by clinical, echocardiographic and biochemical parameters routinely used in clinical practice during or within one year after the start of cancer treatment in ≥ 25 children and adolescents with cancer. Information about study population, treatment, outcomes of diagnostic tests used for cardiotoxicity assessment and risk factors was extracted and risk of bias was assessed.
RESULTS
Our PubMed search yielded 3649 unique publications, 44 of which fulfilled the inclusion criteria. One additional study was identified by scanning the reference lists of relevant studies. In these 45 studies, acute and early-onset cardiotoxicity was studied in 7797 children and adolescents. Definitions of acute and early-onset cardiotoxicity prove to be highly heterogeneous. Prevalence rates varied for different cardiotoxicity definitions: systolic dysfunction (0.0-56.4%), diastolic dysfunction (30.0-100%), combinations of echocardiography and/or clinical parameters (0.0-38.1%), clinical symptoms (0.0-25.5%) and biomarker levels (0.0-37.5%). Shortening fraction and ejection fraction significantly decreased during treatment. Cumulative anthracycline dose proves to be an important risk factor.
CONCLUSIONS
Various definitions have been used to describe acute and early-onset cardiotoxicity due to childhood cancer treatment, complicating the establishment of its exact prevalence. Our findings underscore the importance of uniform international guidelines for the monitoring of cardiac function during and shortly after childhood cancer treatment.
Topics: Humans; Adolescent; Child; Cardiotoxicity; Mitoxantrone; Neoplasms; Heart; Anthracyclines; Polyketides
PubMed: 37710224
DOI: 10.1186/s12885-023-11353-9 -
Biomedicine & Pharmacotherapy =... Jul 2024Mitoxantrone resistant variant of SW620 line was developed, characterized and subsequently used as a model system to determine oncostatin M ability to modulate MDR...
Mitoxantrone resistant variant of SW620 line was developed, characterized and subsequently used as a model system to determine oncostatin M ability to modulate MDR phenomenon. The selection regimen allowed for overexpression of ABCG2 and ABCB1 both at the RNA and protein level, which was further confirmed by functional assays. Oncostatin M supplementation resulted in partial reversal of MDR phenotype by decreasing overexpression of ABCG2 demonstrating for the first time the ability of this cytokine for selective down-regulation of one of MDR proteins.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Mitoxantrone; Drug Resistance, Neoplasm; Humans; Neoplasm Proteins; Oncostatin M; Cell Line, Tumor; Drug Resistance, Multiple; ATP Binding Cassette Transporter, Subfamily B
PubMed: 38850649
DOI: 10.1016/j.biopha.2024.116861 -
Journal of Experimental & Clinical... Nov 2022Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation...
BACKGROUND
Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response.
METHODS
975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed.
RESULTS
We found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8 T and NK cell activation in MDOTS when combined with TGFβ and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8 T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8 T cells and NK cells.
CONCLUSIONS
Combined treatment with low-dose of MTX and anti-TGFβ treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB.
Topics: Humans; Mice; Animals; Programmed Cell Death 1 Receptor; Mitoxantrone; CD8-Positive T-Lymphocytes; Transforming Growth Factor beta; Cell Line, Tumor; Neuroblastoma; Mice, Transgenic; Tumor Microenvironment
PubMed: 36397148
DOI: 10.1186/s13046-022-02525-9 -
Annals of Dermatology Jun 2022Fibroblasts produce collagen molecules that support the structure of the skin. The decrease and hypersynthesis of collagen causes skin problems such as skin atrophy,...
BACKGROUND
Fibroblasts produce collagen molecules that support the structure of the skin. The decrease and hypersynthesis of collagen causes skin problems such as skin atrophy, wrinkles and scars.
OBJECTIVE
The purpose of this study is to investigate the mechanism of mitoxantrone on collagen synthesis in fibroblasts.
METHODS
Cultured fibroblasts were treated with mitoxantrone, and then collagen synthesis was confirmed by reverse transcription-polymerase chain reaction and Western blot.
RESULTS
Mitoxantrone inhibited the expression of type I collagen in fibroblasts at both the mRNA and protein levels. In the collagen gel contraction assay, mitoxantrone significantly inhibited gel contraction compared to the control group. Mitoxantrone inhibited transforming growth factor (TGF)-β-induced phosphorylation of SMAD3. Finally, mitoxantrone inhibited the expression of LARP6, an RNA-binding protein that regulates collagen mRNA stability.
CONCLUSION
These results suggest that mitoxantrone reduces collagen synthesis by inhibiting TGF-β/SMAD signaling and LARP6 expression in fibroblasts, which can be developed as a therapeutic agent for diseases caused by collagen hypersynthesis.
PubMed: 35721328
DOI: 10.5021/ad.2022.34.3.206